1. Field of the Invention
The present invention relates to novel disubstituted or deoxydisubstituted .alpha.-D-lyxofuranosides, their synthesis, and intermediates for preparing these compounds. More specifically, the present invention relates to alkyl, alkoxyalkyl, or aralkyl 2,3-0-(1-methlethylidene) -.alpha.-D-lyxofuranosides unsubstituted or substituted at the 5-position. This invention further relates to the replacement of oxygen at 5-position of lyxofuranosides by N or S to form 5-deoxy-5-amino substituted or 5-deoxy-5-thio substituted lyxofuranosides. These compounds show significant anti-inflammatory and anti-proliferative activity and are useful for treating warm blooded animals and mammals with rheumatoid arthritis, osteoarthritis, scleroderma, systemic lupus erythematosus, autoimmune deficiency syndrome, atopic dermatitis, cancer (particularly colon and melanoma), and psoriasis. Thus, this invention also relates to the pharmaceutical compositions containing lyxofuranoside compounds and methods of treating inflammatory and/or autoimmune disorders.
2. Description of the Related Art
The most reactive functional group in D-lyxose is the anomeric hydroxyl group. A glycoside is formed when the hydrogen atom of an anomeric hydroxyl group is replaced by a substituted or unsubstituted carbon atom. Typically, glycosides are formed either for group protection or as part of the synthesis of a larger molecule. The Fischer Method is particularly effective for synthesizing glycosides from unprotected reducing sugars and low molecular weight alcohols. After the glycosides are formed, various blocking methods are used to block or protect one or more of the hydroxyl group(s) thus leaving one or two hydroxyls free to derivatize. Isopropylidene and benzylidene groups are the most commonly used protective groups in carbohydrate chemistry. These groups are introduced into a molecule under similar conditions; however, the location of the protection can be quite different. The reason for this difference is directly related to the stability of each protected molecule. Since protection normally occurs under conditions which allow reversibility, reaction proceeds until equilibrium is reached. The distribution of products at equilibrium is determined by their relative thermodynamic stabilities. In other words, these reactions are thermodynamically controlled. Benzylidene groups prefer to be part of six-membered ring acetals, while the ketals resulting from acetonation generally are 5-membered rings. The difference is attributed to the effect of the methyl and phenyl substituents on the stability of the particular ring systems. These blocking methods are described in U.S. Pat. Nos. 2,715,121, 4,056,322, 4,735,934, 4,996,195, and 5,010,054 the disclosure of which are incorporated herein by reference. Other blocking methods are described in J. Carbohydr. Chem., 4, 227 (1985); 3, 331 (1984); Methods in Carbohydr. Chem., 1, 191 (1962); 1, 107 (1962); Can. J. Chem., 62, 2728 (1984); 47, 1195, 1455 (1969); 48, 1754 (1970). The therapeutic activity of hexoses and their derivatives are also disclosed in several of the above references.
A well known derivative of .alpha.-D glucose having beneficial therapeutic properties is Amiprilose. HCl, 1,2-0-isopropylidene-3-0-3'-(N',N'-dimethylaminopropyl)-.alpha.-D-glucofur anose. This compound, which is in late Phase III clinical trials, is known to have anti-inflammatory activity and demonstrated utility in managing the signs and symptoms of rheumatoid arthritis.
Unfortunately, while some of the prior art hexose derivatives have shown beneficial therapeutic activity, high doses of these compounds, including Amiprilose. HCl, are often needed to be effective and produce the desired results. Therefore, the prior art derivatives are difficult to prescribe orally. Because, therapy for inflammatory and autoimmune disorders is often midterm and long-term, there is a need to develop potent, non-toxic compounds which can be orally administered to promote ease of treatment and patient compliance.
One object of the present invention, therefore, is to provide a new class of compounds (pentofuranoside derivatives) that exhibit significantly greater potency than available compounds in order to provide ease of treatment, particularly oral administration. It is believed that the compounds of the present invention act by a different mechanism than Amiprilose. HCl and are more selective in their activity.
Another object of the present invention is to provide novel carbohydrate compounds (pentoses) that exhibit significantly greater potency for cancer treatment (particularly melanoma and colon cancer). There is no example available in the literature wherein pentoses, particularly lyxofuranoside derivatives, are used for treating cancer patients (particularly for treating melanoma and colon cancer patients).
Another object of the present invention is to provide a novel class of disubstituted or deoxy disubstituted lyxofuranoside compounds which exhibit anti-inflammatory and anti-proliferative activity. It is also an object of the present invention to provide novel compounds and compositions which are useful in the treatment of warm blooded animals and mammals having anti-inflammatory and/or autoimmune disorders. It is a further object of this invention to provide a novel, simple, and efficient process for preparing alkyl, aryl, aralkyl, or heterocyclic alkyl 2,3-0-(1-methlethylidene)-.alpha.-D-lyxofuranoside compounds.
A still further object of this invention to provide novel compounds that exhibit significantly increased potency over available compounds, such as Therafectin (Amiprilose. HCl), in order to provide ease of oral administration.